Huda Y. Zoghbi, M.D., Director
Marvin Fishman Chair in Pediatric Neurology Research
Professor, Departments of Pediatrics, Molecular and Human Genetics, Neurology, and Neuroscience, Baylor College of Medicine
Investigator, Howard Hughes Medical Institute
Member, Institute of Medicine and National Academy of Sciences
Research focus: Triplet repeat diseases (Spinocerebellar ataxia types 1 and 7); the role of Math1 in development; Rett syndrome; autism.
There are four major research projects in the Zoghbi lab. The first began with the discovery (in collaboration with Harry Orr) of the dynamic mutation underlying spinocerebellar ataxia type 1 (SCA1), a late-onset triplet repeat disease; rigorous use of SCA1 mouse models has revealed the roles of protein misfolding and altered interactions with protein partners that lead to both loss and gain of function of the SCA1 protein, ataxin-1. The SCA1 project was also the lab's first foray into creating an interactome, combining experimental and bioinformatic approaches to creating a protein interaction network that revealed key hub proteins involved in several other ataxias and degenerative diseases.
The second major project sprang from the lab's discovery that mutations in MECP2 form the genetic basis of Rett syndrome, a devastating childhood illness that appears after a period of apparently normal development, robbing girls of acquired language and motor skills and causing a host of other difficulties, including gastrointestinal problems, anxiety, and certain autistic features. Studies of the pathogenesis of Rett syndrome are beginning to provide insight into epigenetic modulation of neuronal function.
Beyond Rett syndrome, mutations as well as duplications involving MECP2 cause a variety of neuropschiatric disorders including childhood-onset schizophrenia and bipolar disorder. These discoveries led the Zoghbi lab into the field of autism, their third major research endeavor. Using biochemical as well as genetic studies, Zoghbi's group is pursuing the identification of shared molecular mechanisms in autism spectrum disorders and the identification of new autism genes.
The fourth area of research in the Zoghbi lab derived from an interest in cerebellar development and led to the discovery of Math1 (mouse atonal homolog 1) in collaboration with the lab of Hugo Bellen (also an NRI investigator; see below). Math1 turns out to be crucial for early development of many neuronal populations outside the cerebellum, including those necessary for proprioception, interoception, breathing, and arousal, as well as inner ear hair cells and the secretory cells of the intestine. Recent work in the lab suggests that Math1 plays a critical role in mediating the genesis of some forms of medulloblastoma, a most prevalent childhood brain tumor.
14-3-3 binding to Ataxin-1 (ATXN1) regulates its dephosphorylation at Ser-776 and transport to the nucleus.
Lai S, O'Callaghan B, Zoghbi HY, Orr HT